Brand Names: U.S.

Lonsurf

Pharmacologic Category

Antineoplastic Agent, Antimetabolite

Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Thymidine Phosphorylase Inhibitor

Pharmacology

Trifluridine, the active cytotoxic component of trifluridine/tipiracil, is a thymidine-based nucleic acid analogue; the triphosphate form of trifluridine is incorporated into DNA which interferes with DNA synthesis and inhibits cell proliferation. Tipiracil is a potent thymidine phosphorylase inhibitor which prevents the rapid degradation of trifluridine, allowing for increased trifluridine exposure (Mayer 2015).

Metabolism

Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY)

Time to Peak

Plasma: ~2 hours

Half-Life Elimination

Trifluridine: 2.1 hours; Tipiracil: 2.4 hours

Protein Binding

Trifluridine: >96% (primarily to albumin); Tipiracil: <8%

Special Populations: Renal Function Impairment

The estimated mean AUC of trifluridine was 31% and 43% higher in patients with mild or moderate renal impairment, respectively, as compared to patients with normal renal function. The estimated mean AUC of tipiracil was 34% and 65% higher, respectively, in patients with mild or moderate impairment as compared to patients with normal renal function.

Special Populations: Hepatic Function Impairment

In a pharmacokinetic study of patients with hepatic impairment, grade 3 or 4 bilirubin elevations were seen in patients with moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment (compared to patients with normal hepatic function). No clinically important differences in mean exposures were noted.

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Note: Obtain blood counts prior to starting each cycle and on day 15 of each cycle. Do not initiate a cycle until ANC ≥1,500/mm3 or febrile neutropenia is resolved, platelets are ≥75,000/mm3, and/or grade 3 or 4 nonhematologic reactions are ≤ grade 1. Trifluridine/tipiracil is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017).

Colorectal cancer, metastatic: Oral: 35 mg/m2 (based on the trifluridine component) twice daily on days 1 to 5 and days 8 to 12 of a 28-day cycle (maximum per dose: trifluridine 80 mg); continue until disease progression or unacceptable toxicity (Mayer 2015). The manufacturer recommends rounding each dose to the nearest 5 mg increment.

Missed dose: Do not take additional doses to make up for missed or held doses.

CrCl <30 mL/minute and ESRD: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Mild impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin <1 to 1.5 times ULN and any AST): No dosage adjustment necessary.

Moderate impairment (total bilirubin >1.5 to 3 times ULN and any AST) or severe impairment (total bilirubin >3 times ULN and any AST): Do not initiate therapy.

Dosing: Adjustment for Toxicity

A maximum of 3 dose reductions are allowed (to a minimum dose of 20 mg/m2). Do not re-escalate dose after it has been reduced.

Hematologic toxicity:

ANC <500/mm3 (uncomplicated or resulting in >1 week delay in the start of the next cycle) or febrile neutropenia: Interrupt therapy; following recovery to ANC ≥1,500/mm3 or resolution of febrile neutropenia, may resume therapy with the dose reduced by 5 mg/m2/dose from the previous dose

Platelets <50,000/mm3 (or resulting in >1 week delay in the start of the next cycle): Interrupt therapy; following recovery to platelets ≥75,000/mm3, may resume therapy with the dose reduced by 5 mg/m2/dose from the previous dose

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Severe and life-threatening bone marrow suppression (anemia, neutropenia, thrombocytopenia) has occurred, including a fatality related to neutropenic infection. In one clinical trial, close to 10% of patients received growth factor support. Monitor blood counts prior to the start of each cycle as well as on day 15, or more frequently if clinically necessary. May require therapy interruption and/or dose reduction.

• Hepatic impairment: Patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) were not included in studies; do not initiate in patients with baseline moderate or severe hepatic impairment. In a pharmacokinetic study in patients with hepatic impairment, several patients with moderate impairment experienced grade 3 or 4 bilirubin elevations.

• Renal impairment: Use with caution. Dosage adjustments due to toxicities may be necessary in patients with moderate impairment. Patients with severe renal impairment (CrCl <30 mL/minute) or end-stage renal disease (ESRD) were excluded from the clinical trial.

• Elderly: Patients ≥65 years experienced a higher incidence of grade 3 and grade 4 neutropenia and thrombocytopenia, as well as increased grade 3 anemia compared to younger patients.

Dosage form specific issues:

• Tablet strength: Trifluridine/tipiracil is available in two tablet strengths (trifluridine 15 mg/tipiracil 6.14 mg and trifluridine 20 mg/tipiracil 8.19 mg); both tablet strengths may be necessary to provide the correct dose. Read labels carefully in order to ensure the appropriate dose is administered. Dosing is based on the trifluridine component. The manufacturer recommends rounding doses to the nearest 5 mg increment.

Monitoring Parameters

Complete blood counts prior to each cycle and on day 15 of each cycle (or more frequently if clinically necessary); signs/symptoms of GI toxicity. Monitor adherence.

Pregnancy Considerations

Based on animal studies and on the mechanism of action, use of trifluridine/tipiracil would be expected to cause fetal harm when used during pregnancy. Females of reproductive potential should use effective contraception during therapy. Males who have female partners of reproductive potential should use condoms during therapy and for at least 3 months following the final dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, mouth sores, mouth irritation, change in taste, or hair loss. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), severe loss of strength and energy, severe nausea, severe vomiting, severe diarrhea, or severe abdominal pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.